Advanced Breast Cancer: Expert Perspectives On Recent Progress - Episode 6

SWOG S1416 and TBCRC 048 Phase 2 Trial Overviews

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Joyce O’Shaughnessy, MD: The SWOG S1416 is really the first data in triple-negative breast cancer that has shown benefit from the addition of a poly [ADP-ribose] polymerase [PARP] inhibitor, which makes it really exciting. I think the genius of that trial was the definition of the breast cancer gene-[BRCA] like population. It needs a prospective follow-up trial of course, but it is a very nice attempt to define this group that may have homologous recombination deficiency beyond the germline BRCA.

The group is not ready for prime time. We do not have veliparib available, but it is a very nice hypothesis generating trial. The lack of benefit from veliparib in the germline BRCA patients stands in contradistinction to the BROCADE 3 where patients received paclitaxel carboplatin with or without veliparib, and the curves were on top of each other for the first 6 to 8, 9 months, and then they split because the patients had the opportunity to stop the chemotherapy and continue veliparib versus placebo as maintenance therapy at their physician's discretion. There was this nice tail on the curve with the veliparib with maintenance strategy, and in the SWOG 1416, there really was not much.

They are waiting still for the data to be fully analyzed, but they really don't think there was very much in the way of a maintenance strategy. We will have to wait and see those data, but that is probably going to explain the difference there. It looks like we may be able to eventually go to a maintenance strategy for veliparib, hopefully based on the Brocades 3 data.

Those are really hypothesis generating for the future, but for our practice, I really want to see what Denise thinks about the TBCRC 048. Is this ready for our practice on Monday morning? The 2 findings were pretty clear from that trial, I thought. What do you think?

Denise Yardley, MD: I agree. I think you know we have been struggling a bit about how to incorporate the PARP inhibitors into practice and for which patients. I think it's an easy thought to think about just our BRCA1 and BRCA2 patients, but now that we have so much profiling and we're looking at now what do we do when we have a somatic BRCA mutation? I think as we step back, this is a great segue into trying to figure out, the approaches to triple negative breast cancer. I think it brings in the role of genetic testing to identify the BRCA1 and BRCA2 for the patients that never received genetic testing in the adjuvant setting.

It is certainly a dialogue I picked up with patients and say, “We have a therapeutic agent that may benefit.” Some patients had been approached in an adjuvant setting and may not have felt strongly about it, but I think I use that as a way of reintroducing it because there is a therapy tied to it. I think likewise for profiling patients, it is another trigger of maybe we don't always find a target that's actionable.

When we see this data, you think there is a reason to profile these tumors and try to identify them even though they're not a germline but are somatic mutations. I think we are going to continue to evolve with some of the other mutations like the ataxia-Telangiectasia mutated and checkpoint kinase 2 to be able to continue to increase the armamentarium for these triple negative breast cancer patients and be able to use these targeted agents as single agents here with the PARP, to look at it, and then again utilizing in our triple-negatives testing for the PD-L1 with SP142 that we've touched on, to embrace that population that's going to be eligible for the consideration of immunotherapy.

I think now the hard part may be in how do we sequence someone that has a somatic or germline mutation and may be PD-L1 positive? It kind of opens a Pandora's box in a nice way. I think looking at survival data is important, so that may be a segue of looking at how to use or sequence if you have a PD-L positive and a BRCA positive somatic or germline patient. I think it just broadens the horizons of how we think of triple negative, and we have kind of learned that in itself is a very heterogeneity population.

It merits an investigation and to tease out the subpopulations in triple-negative breast cancer because I think we have exciting targets in agents to improve the outcomes from these patients and to continue offering therapeutic choices that could keep these patients and quality of life and with stable disease.

Joyce O’Shaughnessy, MD:Thank you. The time for next generation sequencing is here, and reintroducing it to the clinic, reintroducing the idea of germline testing now even more with the PALB2 data. How about you Hope. Are you thinking about the germline PALB2s as a somatic BRCA? Would you consider using olaparib for those patients?

Hope S. Rugo, MD, FASCO:I already have. We participated in that trial, and I enrolled our only patient at our institution, who had PALB2 mutation and did have a prothrombin ratio, but then it rapidly progressed in brain. I'm really interested in trying to get these drugs earlier in the course of therapy, and a lot of these patients with mutated PALB2 have hormone or are hormone receptor positive. I think the OlympiAD trial would be really helpful for us in the adjuvant setting to try and better understand if we can take patients with high-risk disease and change their outcome by giving these agents earlier.

That would include patients with PALB2 mutations. I think, to Denise's point, looking at the somatic BRCA-mutant patients and other mutations that cause DNA repair defects is going to be interesting. This trial underneath Nadine Tung's leadership through our consortium will expand and include additional patients and expand to various groups, so that we'll have even more data.

I think it's really important and having these agents is important as well. I think for the SWOG is interesting to me because the hazard ratio for this BRCA-like group was 0.53, but the difference actually in progression-free survival was very small. It was just about 1.7 months, and they did suggest this survival difference although it wasn't statistically significant; I think their numbers are really small.

I wonder how many of these patients might have had somatic mutations in BRCA versus those who had the HRD [homologous recombination deficiency] defect alone without somatic mutations. You know it's going to be interesting over time to see that. I also wonder if some of the differences seen here versus the Brocades trial have to do with the poor tolerance of cisplatin. Having seen patients who enrolled on that trial who were miserable on the cisplatin, you wonder whether or not the choice of the DNA damaging chemotherapy is important here as well.

Transcript edited for clairty.